TW201740928A - Ophthalmic compositions - Google Patents

Abstract

Provided herein is an ophthalmic composition including a therapeutic active agent and an anti-inflammatory agent, in which the active agent is at least about 0.01% w/v of chlorhexidine, derivatives, or analogues of chlorhexidine, or a pharmaceutically acceptable salt, solvent, hydrate, or polymorph thereof. Methods for treating or preventing ocular disease or infection in a subject in need thereof are also provided. The method may include administering to an eye of a subject an ophthalmic composition including chlorhexidine, derivatives, or analogues of chlorhexidine, or a pharmaceutically acceptable salt, solvent, hydrate, or polymorph thereof, and an anti-inflammatory agent. The chlorhexidine, derivatives, or analogues of chlorhexidine, or a pharmaceutically acceptable salt, solvent, hydrate, or polymorph thereof and the anti-inflammatory agent are present in an amount effective to treat or prevent the ocular disease or infection in a subject in need thereof.

Description

Ophthalmic composition

The present disclosure relates to an ophthalmic composition comprising chlorhexidine and an anti-inflammatory agent as an active agent, and a method of treating or preventing an ocular disease or infection.

It is often difficult for doctors to determine the type of microbe that causes an eye disease or infection (eg, conjunctivitis). Most doctors who diagnose eye diseases or infections (eg, infectious conjunctivitis or corneal disease) do not have easy access to the hospital's microbiological facilities to accurately diagnose the disease. In addition, microbiology laboratories are often not good at identifying nuances related to infections in eye samples. For these reasons, most conjunctivitis is assumed to be bacterial without conventional culture and is treated with bacterial infections, such as the use of ophthalmic antibiotic solutions. However, antibiotics do not have activity against other causes of conjunctivitis, including, for example, viruses that may be misdiagnosed or undiagnosed, and A. sinensis.

There is a need for an ophthalmic composition that can treat at least one ocular tissue (e.g., conjunctiva or cornea) or an infectious ocular composition that may come from a variety of different sources (e.g., bacteria, mold, or viruses). Antibacterial/anti-inflammatory compositions suitable for post-operative viral, mold, mycobacterial and amoeba infections are also needed.

Particularly provided herein are ophthalmic compositions comprising a therapeutic active agent and an anti-inflammatory agent, wherein the active agent is at least about 0.01% w/v of chlorhexidine, a chlorhexidine derivative or the like, or A pharmaceutically acceptable salt, solvent, hydrate or allotrope.

The concentration of chlorhexidine, a chlorhexidine derivative or analog, or a pharmaceutically acceptable salt, solvent, hydrate or allotrope thereof in the ophthalmic composition may be from about 0.01% to about 1.0% ( B).

In one embodiment, the one or more anti-inflammatory agents can comprise a steroid or a non-steroidal anti-inflammatory agent or both. Steroids may include, for example, dexamethasone, difluprednate, fluormethalone, loteprednol etabonate, prednisolone acetate , prednisolone phosphate, or a combination thereof. For example, the anti-inflammatory agent may comprise ketotifen fumarate, diclofenac sodium, flurbiprofen sodium, ketorolac tromethamine, supprofen. ), celecoxib, naproxen or rofecoxib, or a combination thereof. The concentration of the anti-inflammatory agent can range from about 0.025% to about 2% (weight/volume).

In another embodiment, the ophthalmic composition can further comprise a preservative. The preservative may comprise benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, disodium edetate, sorbic acid or Onam M, or a combination thereof.

In another embodiment, the ophthalmic composition can further comprise a pharmaceutically acceptable carrier or an ophthalmic vehicle.

In a specific embodiment, the ophthalmic composition may further comprise a cosolvent. The cosolvent may comprise polysorbate 20, polysorbate 60, polysorbate 80, Pluronic F-68, Pluronic F-84, Pluronic P-103, cyclodextrin, or a combination thereof. The cosolvent may be present at a concentration of from about 0.01% to about 2% (weight/volume).

In another embodiment, the ophthalmic composition can further comprise a viscosity agent. The viscosity agent may comprise polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose or hydroxypropyl cellulose, or a combination thereof. The thickener may be present at a concentration of from about 0.01% to about 2% (weight/volume).

Alternatively, the ophthalmic composition can be formulated as a solution, suspension, semi-liquid, emulsion, ointment, cream, foam gel, powder or controlled release/sustained release solution.

In yet another embodiment, the present disclosure provides methods of treating or preventing an ocular disease or infection in a subject in need thereof. The method comprises administering an ophthalmic composition comprising a therapeutic active agent and an anti-inflammatory agent to the eye of the subject, wherein the active agent is effective for treating or preventing an eye disease in a subject in need thereof, at least About 0.01% w/v of chlorhexidine, a derivative or analog of chlorhexidine, or a pharmaceutically acceptable salt, solvent, hydrate or allotrope thereof.

On the one hand, ophthalmic compositions for treating or preventing ocular diseases or infections can be formulated into solutions, suspensions, semi-liquids, emulsions, soft Cream, cream, foam gel, powder or controlled release/sustained release solution.

Ophthalmic compositions can be used to treat ocular disorders, which may include conjunctivitis, tendinitis or keratitis. Furthermore, the amount of ophthalmic composition can be effective in the prevention or treatment of post-surgical infections. An ophthalmic composition comprising a derivative or analog of chlorhexidine, chlorhexidine, or a pharmaceutically acceptable salt, solvent, hydrate or allotrope of chlorhexidine, a derivative or analog thereof, and The anti-inflammatory agent may be administered usually in an amount of from about 0.001 mg/eye to about 5.0 mg/eye, or the ophthalmic composition may be administered in an amount of from about 50 μL to about 80 μL per eye.

In a specific example, the source of the ocular disease or infection is bacteria, mycobacteria, mold, virus or amoeba.

Particularly provided herein are compositions and methods for treating ocular diseases or infections. The ophthalmic composition comprises a therapeutic agent, such as a derivative or analog of chlorhexidine, chlorhexidine, or a pharmaceutically acceptable salt, solvent, hydrate or allotrope of chlorhexidine, a derivative thereof or the like. And anti-inflammatory agents (eg, steroid or non-steroidal anti-inflammatory agents). In a specific embodiment, the composition is inhibited (eg, topically applied) to inhibit the viability of at least one microorganism. A chlorhexidine, a derivative or analog of chlorhexidine, or a pharmaceutically acceptable salt, solvent, hydrate or allotrope of chlorhexidine, a derivative or analog thereof, may be from about 0.01% to about 1.0% w The amount of /v is combined with an anti-inflammatory agent.

Compared with current methods and compositions, including chlorhexidine Method and composition of a chlorhexidine derivative or analog, or a pharmaceutically acceptable salt, solvent, hydrate, or allotrope, derivative or analog thereof, and anti-inflammatory agent of chlorhexidine Therapies provide significant advantages for treating ocular diseases and infections. The use of chlorhexidine and anti-inflammatory agents, respectively, to treat ocular diseases and infections is often problematic and unfavorable to the subject. For example, mild and severe sensitization reactions have raised concerns about the safety of chlorhexidine. In 1998, the FDA issued a public health bulletin to warn health care professionals about the potential for severe allergic reactions to chlorhexidine-containing medical devices.

Because human eyes are more delicate than the surface of the skin or oral mucosa, the use of chlorhexidine in the eye is more risky and is limited by the known chlorhexidine that can irritate the eyes. There is a report on the use of chlorhexidine as a disinfectant for contact lenses, which is not completely rinsed before wearing and causes eye damage. Even in compositions that may contain chlorhexidine, it is often used as a disinfectant (eg, for oral care and oral hygiene). Further, in certain compositions, chlorhexidine is most often used as a preservative at low concentrations (e.g., less than 0.01%).

Injury caused by accidental administration of chlorhexidine has been reported. For example, Van Rij et al . describe the accidental administration of chlorhexidine to patients undergoing ophthalmic surgery resulting in immediate corneal edema leading to bullous keratopathy; all affected patients require a corneal transplant. See van Rij, G., et al., Doc. Ophthalmol. 1995; 90(1): 7-14. Moreover, Tabor et al. also described 4 cases of topical chlorhexidine that would be considered acceptable for accidental corneal damage resulting in irreversible corneal damage. See Tabor, E., et al. JAMA. 1989 Jan 27; 261(4): 557-8. Because of the conventional toxicity of chlorhexidine to the eye, there are no chlorhexidine ophthalmic drops formulations that have been marketed.

Because steroids are known to increase the sensitivity of certain infections, care is also taken to investigate the use of steroids alone in the setting of ocular infections and/or eye diseases. Topical corticosteroids are commonly used to control ocular inflammation, however, their mechanism of action involves inhibition of the immune response and subsequent tissue destruction which may be inflammatory. Topical steroids applied to the eye reduce the production of constituent proteins of the inflammatory cascade, reduce vascular permeability, reduce the production of inflammatory cytokines, and reduce the intensity of soluble inflammatory factors through well-described genomic and non-genetic mechanisms. It inhibits the production of phase protein, reduces leukocyte migration and increases the stability of cell membranes. Through all of these mechanisms, topical administration of steroids reduces the toxic activation products to the eye, including the gelatinase, collagenase, and matrix metalloproteinase families of proteins. As these potentially toxic substances decrease, there is an increased risk of long-term infections and potential infections. Care must therefore be taken when prescribing topical ophthalmic steroids for potential infections, as it may limit the body's ability to fight infection. Moreover, studies have confirmed that both weak and strong steroids prolong the spread of the virus compared to the control group.

Steroids can aggravate the course of infection secondary to mycobacterial, viral or fungal infections. In the case of infection with Acanthamoeba falciparum, this is a well-documented example: multiple case reports indicate that pre-treatment of ocular aberrations of Acanthamoeba falciparum infection is associated with visual deterioration outcomes. Therefore, due to these significant risks, it is recommended to use a combination of antibacterial-steroid drugs for ocular infections only with the careful observation of trained ophthalmologists. In fact, the combination of Tobradex ^® (Alcon), tobramycin and dexamethasone, the most commonly prescribed compound antibacterial-steroid drug, specifically lists 'corneal and conjunctival viral diseases, mycobacterial infections and fungal infections 'Absolute contraindications for its use. Obviously, these combination drugs are not intended for use in infectious conjunctivitis where the source of the disease is unconfirmed.

The composition described herein comprises a combination of chlorhexidine, a derivative or analog of chlorhexidine, or a pharmaceutically acceptable salt, solvent, hydrate or allotrope thereof and an anti-inflammatory agent for treatment Reducing, preventing, and/or alleviating the ocular condition of a patient or a subject in need thereof. Such ocular conditions include ocular diseases (eg, infection of one or more ocular tissues, conjunctiva, or cornea) including, for example, bacteria, mycobacteria, viruses, molds, and amoeba-causing eyes. Conjunctival or corneal infection. In addition, the ophthalmic composition can also be used for infective prevention and inflammation control of a patient after an ophthalmic surgery or ophthalmic procedure, for example, including intraocular injection.

definition

All technical or scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this disclosure belongs, unless otherwise indicated. The following references provide a general definition of the many terms used in the present invention by the skilled artisan: The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). Unless otherwise stated, the following terms as used herein have the following definitions.

The term "or" as used herein is understood to be inclusive unless specifically stated or clear from the context. Unless specified or from It is clear from the context that the terms "a", "an" and "the" are used in the singular or plural.

The term "about" as used herein is to be understood to be within the normal tolerances of the art, such as within 2 standard deviations of the mean, unless specifically stated or clear from the context. "About" is understood to mean 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05% or Within 0.01%. All numerical values provided herein are modified by the term "about" unless it is clear from the context.

The term "administration" or "administering" means the act of providing an agent of the present specific embodiment or a pharmaceutical composition comprising a specific agent to an individual in need of treatment.

By "co-administered" is meant the administration of the compositions described herein, just before, or just after, the administration of the additional therapy. The compounds or compositions of the present disclosure may be administered alone or co-administered to a patient. Co-administration refers to the administration of a compound comprising the same or sequential, alone or in combination (more than one compound or agent). The formulation may also be combined with other active substances as needed.

As used herein, "administered sequentially" includes the administration of two agents (eg, a compound or composition described herein) that occur separately or not on the same day (eg, on consecutive days).

As used herein, "simultaneous administration" includes at least partial overlap. For example, when two agents are administered simultaneously (e.g., any agent or agent having biological activity as described herein), the administration takes place within a certain desired period of time. Administration of the agent can begin and end on the same day. As long as the two agents are taken at least once on the same day, the administration of one agent can also be in the second Before administration of the drug. Similarly, as long as both agents are administered at least once on the same day, administration of one agent may be beyond the administration of the second agent. The bioactive agent/agent does not have to be administered simultaneously and is taken at the same time each day.

As used herein, "intermittent administration" includes administration of the agent for a period of time (which may be considered a "first dose"), followed by a period of no administration of the agent or a lower maintenance dose (which may be considered a "discontinuation period") followed by The agent is administered again over a period of time (which may be considered a "second phase administration"). Generally, during the second phase of administration, the dosage level of the agent will be consistent with the dosage level administered during the first phase of administration, but may be increased or decreased as required by the medical need.

As used herein, an "effective amount" or "therapeutically effective amount" is an amount sufficient to affect a desired physiological response, such as a beneficial result comprising a clinical outcome. Therefore, the "effective amount" depends on the context in which it is applied. The effective amount can vary depending on factors well known in the art, such as the disease condition, age, sex, and weight of the individual being treated. The dose may be administered in several divided doses per day or may be proportionally reduced depending on the emergency indication of the treatment situation. In addition, the compositions/formulations of the present disclosure can be administered as often as needed to achieve a therapeutic amount.

The term "anti-inflammatory agent" as used herein means an agent that is capable of reducing inflammation in a subject. As is known in the art, the anti-inflammatory agent can be a steroid or a non-steroid.

The term "disinfecting" as used herein means to attenuate the nature of infection, sepsis or spoilage that has been established in living tissue or skin. In a specific example, disinfection means the property of killing a plurality of microorganisms, such as one or more bacteria, molds, viruses or protozoa.

The term "antibacterial agent" means killing, inhibiting or preventing microorganisms Microbes/microorganisms such as bacteria, molds, and viruses.

In the present disclosure, "comprises", "comprising", "containing", and "having" have the meanings given by the US Patent Law and may mean "includes", " "consisting essentially of" or "consists essentially" has the same definition and terminology conferred by US patent law as being open, allowing for the exclusion of There are, as far as possible, the presence of the basic or novel features not recited, but does not include prior art embodiments.

The term "inflamed or inflammatory condition of the eye" as used herein means an inflammatory eye disease or any inflammatory condition of the external tissues surrounding the eyes and eyes, such as infection, injury, radiation, surgery or injury to the tissues surrounding the eyes or eyes. And cause inflammation. Inflammatory eye disease is caused by leakage of blood vessels in the eye or inflammation of the eye. Examples of conditions associated with inflammation of the eye include, but are not limited to, surgical trauma; dry eye syndrome; allergic conjunctivitis; viral conjunctivitis; bacterial conjunctivitis; tendinitis; anterior uveitis; chemical injury; Or thermal burns; or foreign body intrusion, signs and symptoms of eye problems (eg, pain in the eyes or around, especially in the eyes accompanied by pain (with or without rotation), redness, extreme light sensitivity, halo (color around the lamp) Circle or halo), bulging (protrusion) or swelling of the eye tissue, escaping, scarring or tears; eyelids stick together, especially during awakening, in front of the eye (colored part) Upper) or white bloody bleeding; cataract; pain or inflammation associated with wearing contact lenses; cornea after cataract surgery Pathological corneal edema, corneal opacity, corneal transplantation, corneal ulcer, dry eye syndrome, malnutrition, conditions associated with excimer laser light treatment for keratectomy, herpes simplex keratitis, keratoconus, pterygium, Recurrent erosive syndrome; eyeball rotation disorder; glaucoma; eye tumor, eye plastic surgery (eg, cosmetic surgery, eyeball removal, eyelid and eyelid injury, valgus valgus, valgus varus, Graves' disease, involuntary eyelids) Inflammatory); conditions associated with refractive surgery; and retinopathy.

The term "inhibiting" as used herein means preventing, reducing, slowing or preventing. In particular, the composition is believed to inhibit the activity of one or more microorganisms when the number or rate of processes or reactions occurring in the presence of the composition is reduced by at least about 10% compared to the amount or rate without the composition. In another embodiment, the composition inhibits the process or reaction when the number or rate of processes or reactions occurring in the presence of the composition is reduced by at least about 20% compared to the amount or rate without the composition. In other embodiments, the amount or rate of activity occurring in the presence of the composition is reduced by at least about 25%, about 30%, about 40%, about 50%, about 60%, about the amount or rate at which no composition is present. At 70%, about 75% or about 80%, the composition is believed to inhibit the viability of one or more microorganisms. In other specific examples, the composition is believed to inhibit the viability of one or more microorganisms, i.e., prevent their development.

As used herein, "microorganism" or "microbe" means a microbial microorganism which may be a single cell or a multi-cell. Microorganisms can contain all bacteria, archaean and protozoan species. This group also contains mold, algae and certain animals of some species. In a specific example, the virus is also classified as a microorganism.

The term "ophthalmic composition" as used herein means a composition to be applied to the eye or its associated or surrounding tissue such as, for example, the eyelid or the cornea. The term also encompasses compositions for the therapeutic treatment of conditions in the eye itself or in tissues surrounding the eye. The ophthalmic composition can be applied by other techniques known to those skilled in the art, such as injection into the eye. Examples of suitable topical ocular administrations include administration of ophthalmic drops and spray formulations. A more appropriate local ocular route of administration is subconjunctival injection. The composition can also be provided to the eye area or behind the eyelids.

As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, paints, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. The type of vector can be selected based on the desired route of administration. The pharmaceutically acceptable carrier comprises a sterile aqueous solution or dispersion and a sterile powder for the instant formulation of a sterile topical solution or dispersion. The use of such media and agents in pharmaceutically active substances is well known in the art. Unless any conventional medium or agent is incompatible with the composition (eg, chlorhexidine, a derivative or analog of chlorhexidine, or a pharmaceutically acceptable salt, solvent, hydrate or allotrope thereof), Its use in the ophthalmic compositions of the present disclosure will be covered.

The terms "prevent", "preventing", "prevention", "prophylactic treatment" and the like as used herein mean reducing, but not at risk, or developing obstacles or The likelihood of a disorder or condition progression in a subject with a condition.

The scope provided herein is to be understood as a shorthand for all values in the range. For example, it should be understood that the range of 1 to 50 includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, Any of the groups consisting of 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 The number, combination or sub-range of numbers and all intermediate decimal values between the above integers are, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. Regarding the sub-range, consider the "nested sub-range" that extends from either end of the range. For example, nested sub-ranges of exemplary ranges 1 to 50 may include 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20 in the other direction. And 50 to 10.

"Subject" or "patient" means a human or non-human animal, such as a mammal. "Subject" means any animal, including horses, dogs, cats, pigs, goats, rabbits, hamsters, monkeys, guinea pigs, rats, mice, lizards, snakes, sheep, cattle, fish, and birds. A human subject can be referred to as a patient.

As used herein, "treat", "treating" or "treatment" and other grammatical equivalents encompasses alleviating, alleviating, ameliorating or preventing a disease, condition (eg, conjunctivitis or other eye disease or Infection) or symptoms, prevention of additional symptoms, improvement or prevention of the underlying metabolic cause of the symptoms, inhibition of the disease or condition, such as prevention of the development of the disease or condition, relief of the disease or condition, regression of the disease or condition, relief A condition caused by a disease or condition or a symptom that stops the disease or condition, and is meant to include prevention. The term further encompasses achieving therapeutic benefit or preventive benefit. Therapeutic benefit means the eradication or improvement of the potential disorder being treated. Moreover, achieving the therapeutic benefit of eradication or improvement of one or more physiological symptoms associated with a potential disorder Improvements are seen in the patient, although the patient may still be afflicted with potential obstacles.

The terms "prevent", "preventing" or "prevention" and other grammatical equivalents as used herein are meant to prevent development, occurrence, obstruction or avoidance of a disease or condition and to reduce the onset of symptoms. Prevention can be complete (i.e., no detectable symptoms) or partial, such that less symptoms are observed that may occur than without treatment. The term further includes preventive benefits. For the disease or condition to be prevented, the composition can be administered to a patient at risk of developing a particular disease, or to a patient having a physiological condition of one or more diseases, although the diagnosis of the disease has not yet been made.

As used herein, "viscosity" means the flow resistance of a fluid.

The term "percent by weight" or "% (w/w)" means the percentage of the component in the solution calculated on the basis of the weight of the component and the solvent. For example, a 1% (w/w) solution of the component should have 1 g of the component dissolved in 100 g of solvent. The term "volume percentage" or "% (v/v)" means the percentage of the component in the solution calculated based on the volume of the component and the solvent. For example, a 1% (v/v) solution of the component should have 1 ml of the component dissolved in 100 ml of solvent. The term "weight/volume percentage" or "% (w/v)" means the percentage of the component in the solution based on the weight of the component and based on the volume of the solvent. For example, a 1.0% (w/v) solution of the component should have 1 g of the component dissolved in 100 ml of solvent.

composition

When the ophthalmic composition is administered to the eye, the ophthalmic composition comprises an effective amount of a chlorhexidine, a derivative or analog of chlorhexidine, or a pharmaceutically acceptable salt, solvent, hydrate or allotrope thereof, And at least one anti-inflammatory agent that inhibits the viability of one or more microorganisms. In a specific example, Ophthalmic compositions are used to treat ocular diseases.

Chlorhexidine

In a specific example, chlorhexidine (N,N'''-1,6-hexanediylbis[N'-(4-chlorophenyl)(imidodicarbodiimide diamine) (imidodicarbonimidic diamide))]), a derivative or analog thereof, or a pharmaceutically acceptable salt of chlorhexidine (such as, by way of non-limiting example, dihydrochloride, diacetate, and digluconate), solvent, Hydrates, and/or allotropes, derivatives or analogs thereof, as therapeutic active agents. In a specific embodiment of the present disclosure, the ophthalmic composition comprises an active agent, such as chlorhexidine or a derivative or analog thereof, or a pharmaceutically acceptable salt of chlorhexidine (such as, by way of non-limiting example, dihydrochloride) , diacetate and digluconate), solvents, hydrates, and/or allotropes, derivatives or analogs thereof.

Chlorhexidine, for example, is effective against Gram-positive and Gram-negative organisms, facultative anaerobic bacteria, aerobic bacteria, yeast, A. sinensis, viruses, and mycobacteria.

Non-limiting examples of chlorhexidine derivatives may be dibiguanide, biguanide, oxime, aryl derivatives, alkyl derivatives, alicyclic derivatives. For example, the chlorhexidine derivative may be an N' derivative of p-chlorophenyl biguanide, p-chlorophenyl biguanide, and p-chlorophenyl hydrazine.

The chlorhexidine, chlorhexidine derivative or analog, or the pharmaceutically acceptable salt, solvent, hydrate or allotrope, derivative or analog thereof may be used in any suitable amount or concentration. In one aspect, a chlorhexidine, a derivative or analog of chlorhexidine in the ophthalmic composition, or a pharmaceutically acceptable salt, solvent, hydrate or allotrope of chlorhexidine, The concentration of its derivative or analog is from about 0.01% to about 1.0% (weight/volume (w/v)). In a specific embodiment, a chlorhexidine, a chlorhexidine derivative or the like in the composition, or a pharmaceutically acceptable salt, solvent, hydrate or allotrope of a chlorhexidine, a derivative or the like thereof The concentration can be from about 0.01% (w/v) to about 0.02% (w/v); from about 0.01% (w/v) to about 0.03% (w/v); from about 0.01% (w/v) to about 0.04. % (w/v); from about 0.01% (w/v) to about 0.05% (w/v); from about 0.01% (w/v) to about 0.06% (w/v); about 0.01% (w/v) ) to about 0.07% (w/v); about 0.01% (w/v) to about 0.08% (w/v); about 0.01% (w/v) to about 0.09% (w/v); or about 0.01 %(w/v) to about 1.0% (w/v). In a specific embodiment, a chlorhexidine, a chlorhexidine derivative or the like in the composition, or a pharmaceutically acceptable salt, solvent, hydrate or allotrope of a chlorhexidine, a derivative or the like thereof The concentration can be about 0.01% (w/v), about 0.02% (w/v), about 0.03% (w/v), about 0.04% (w/v), about 0.05% (w/v), about 0.06. % (w/v), about 0.07% (w/v), about 0.08% (w/v), about 0.09% (w/v) or about 1.0% (w/v).

Anti-inflammatory agent

In certain aspects, the disclosed ophthalmic compositions comprise one or more anti-inflammatory agents. The anti-inflammatory agent can be, for example, a steroid anti-inflammatory agent or a non-steroidal anti-inflammatory agent. Any suitable steroid anti-inflammatory agent or non-steroidal anti-inflammatory agent may be included in the composition.

Non-limiting examples of steroid anti-inflammatory agents include 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, betamethasone Dipropionate (betamethosone) Diproprionate), budesonide, chloroprednisone, clobetasol, corticosterone, cortisone, cortivazol, dextrov Deflazacort, desonide, dexamethasone alcohol, dexamethasone sodium phosphate, diflorasone, dutasteride, fluticasine pivalate Flumethasone pivalate, fluocinonide, fluorometholone acetate, fluorometholone alcohol, fluticasone propionate, halcinonide , halobetasol propionate, halometasone, halopedone acetate, hydrocortamate, hydrocortisone, hydrofluorothiazide (hydroflumethiazide), lotiprendol etabonate, medrysone, prednisolone acetate, prednisolone sodium phosphate, rimexolone, hydrocortisone, Hydrogenation Body pine acetate, lodoxamide tromethamine, difluprednate, or a combination thereof. In one aspect, the steroid anti-inflammatory agent can be a corticosteroid drug such as prednisolone acetate.

Non-limiting examples of non-steroidal agents include aspirin (Anacin, Ascriptin, Bayer, Bufferin, Ecotron, Excedrin), choline salicylate and magnesium (CMT, Tricosal, Trilisate), choline salicylate (Arthropan), celecoxib, potassium diclofenac (Cataflam), diclofenac sodium (Voltaren, Voltaren XR), diclofenac Sodium and misoprostol (Arthrotec), diflunisal (Dolobid), etodolac (Lodine, Lodine XL), fenoprofen calcium (Nalfon) ), flifiprofen (Ansaid), ibuprofen (Advil, Motrin, Motrin IB, Nuprin), indomethacin (Indocin, Indocin SR), ketoprofen (Actron, Orudis, Orudis KT, Oruvail) ), ketotifen fumarate, ketorolac tromethamine, magnesium salicylate (Arthritab, Bayer Select, Doan's Pills, Magan, Mobidin, Mobogesic), meclofenamate Sodium) (Meclomen), mefenamic acid (Ponstel), meloxicam (Mobic), nabumetone (Relafen), naproxyn (Naprelan), naproxen sodium (Aleve, Anaprox), oxaprozin (Daypro), piroxicam (Feldene), rofecoxib (Vioxx), salsalate (Amigesic, Anaflex 750, Disalcid, Marthritic, Mono-Gesic, Salflex, Salsitab), sodium salicylate, sulindac (Clinoril), tolmetin sodium (Tolectin), sulphonate, valdecoxib (val Decoxib) (Bextra), or a combination thereof.

The anti-inflammatory agent can be used in any suitable amount. For example, in some embodiments, the concentration of such an anti-inflammatory agent can range from about 0.025 to about 2.0 weight percent. The anti-inflammatory agent can be present in an amount between about 0.025, about 0.05, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 1.0, and about 2.0 weight percent, or any amount between these amounts. In particular embodiments, the concentration of the anti-inflammatory agent can range from about 0.05% (w/v) to about 1.0% (w/v).

microorganism

In one aspect, the disclosed ophthalmic compositions are effective to inhibit the viability of one or more microorganisms. These microorganisms include, for example, bacteria, molds, viruses, and protozoa. In addition, the ophthalmic composition inhibits the viability of two or more microorganisms (eg, treating ocular diseases and infections derived from bacterial and viral infections).

In one embodiment, the ophthalmic composition effectively inhibits the viability of one or more microorganisms, wherein the microorganism comprises bacteria. The exemplified bacterial microorganisms may include Gram-positive and Gram-negative aerobic bacteria and anaerobic bacteria. Non-limiting examples of such bacteria include Bacillus megaterium , Enterobacter gergoviae , Aeromonas hydrophila , Aquaspirillum gracile , and fine nitrite arcs. Nitrosovibrio tenuis , Enterobacter gergoviae , Kurthia gibsonii , Cytophaga agarovorans , Scytonema , Enterobacter Gergoviae ), Bacillus acidocaldarius , Cytophaga succinicans , Aquaspirillum itersonii , Azomonas insignis , Aquaspirillum Aquaticum ), Gardnerella vaginalis , Staphylococcus epidermis , Staphylococcus aureus , Staphylococcus hominis , Pseudomona fluorsecens , agile Pseudomonas facilis , Pseudomonas syringae ( Pseudomonas aeruginosa), clayey marcescens (Serratia marcescens), Propionibacterium acnes (Propionibacterium acne), Enterococcus faecalis (Enterococcus faecalis), Streptococcus pneumoniae (Streptococcus pneumoniae), Haemophilus influenzae (Haemophilus influenza), colon Escherichia coli , Moraxella catarrhalis , Mycoplasma pneumoniae , Mycobacterium tuberculosis , Mycobacterium avium , Mycobacterium tuberculosis Mycobacterium gordonae clade , Mycobacterium kansasii clade , Mycobacterium nonchromogenicum/terrae clade , Mycolactone-producing mycobacteria , Mycobacterium simiae clade , Mycobacterium chelonae clade , Mycobacterium fortuitum clade , Mycobacterium parafortuitum clade and female Mycobacterium vaccae clade . The composition inhibits the viability of one or more bacteria.

In another embodiment, the ophthalmic compositions of the present invention effectively inhibit the viability of one or more microorganisms, one of which comprises a mold. Non-limiting examples of mold comprises Candida albicans (Candida albicans), ringworm (Trichophyton mentagrophytes), black aspergillus (Aspergillus niger), Cryptococcus neoformans (Cryptococcus neoformans), Gatti Cryptococcus (Cryptococcus gatti), Audubon Microsporum audouinii , Microsporum canis , Microsporum canis var. distortum , Microsporum cookei , Microsporum equinum , Microsporum ferrugineum , Microsporum fulvum , Microsporum gallinae , Microsporum gypseum , Microsporum nanurn , peach color Bacillus (Microsporum persicolor), Ji Teli section of skin bacteria (Arthroderma gertleri), the light section muddy skin bacteria (Arthroderma gloriae), Arthroderma gruby, Epidermophyton floccosum (Epidermophyton floccosum) and color aspergillus fumigatus (Aspergillus fumigatus) . The composition inhibits the viability of one or more molds.

In another embodiment, the ophthalmic composition inhibits the viability of one or more microorganisms, one of which comprises a virus. Non-limiting examples of viruses include adenovirus, human papillomavirus (HPV), human immunodeficiency virus-1 (HIV-1), herpes (such as herpes simplex virus-1 or herpes zoster), Epstein- Bar virus, poliovirus (such as poliovirus-1), human cytomegalovirus, and varicella zoster virus. The composition inhibits the viability of one or more viruses.

In still another embodiment, the ophthalmic composition inhibits the viability of one or more microorganisms, one of which comprises a protozoan (Amoeba). Non-limiting examples of such protozoa include Acanthamoeba keratitis , Trichomonas vaginalis , Leishmania major , Leishmania major , Leishmania major ( Leishmania tropica ), Leishmania aethiopica , Leishmania Mexicana , and vian genus Leishmania ( Viannia braziliensis ). The composition inhibits the viability of one or more protozoa.

Pharmacologically acceptable carrier

The compositions herein may also comprise a pharmaceutically acceptable carrier or ophthalmic vehicle. The phrase "pharmaceutically acceptable carrier" or "vehicle" or "pharmaceutically acceptable vehicle" means a delivery vehicle for a composition (eg, an ophthalmic composition). Exemplary carriers include saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof.

Cosolvent

The ophthalmic composition can comprise a cosolvent. The solubility of the components of the composition may be enhanced by the use of a surfactant or other suitable co-solvent in the composition. Such cosolvents include, but are not limited to, polysorbate 20, polysorbate 60, polysorbate 80, Pluronic F-68, Pluronic F-84, Pluronic P-103, cyclodextrin, and other suitable Medicament, or a combination thereof. The cosolvent can be used in any suitable amount. In one aspect, such cosolvents are used at a concentration of from 0.01% to 2% by weight.

preservative

The composition may contain a preservative such as an antimicrobial preservative. Suitable preservatives may, for example, be hydroxychloroaniline, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, disodium edetate, sorbic acid, Onamer M Polyquat, cetyl bromide, cetylpyridinium chloride, benzyl bromide, EDTA, phenylmercuric nitrate, phenylmercuric acetate, thimerosal, merthiolate, boric acid Phenylmercury, polymyxin B sulfate, methyl and propyl parabens, quaternary ammonium chloride, sodium benzoate, sodium propionate and sodium perborate, and other reagents well known to those skilled in the art, or Its combination.

The preservative can be used in any suitable amount. In some embodiments, such preservatives are present at a concentration of from about 0.001% to about 1.0% by weight. The preservative can be present in an amount between about 0.001, about 0.002, about 0.003, about 0.004, about 0.005, about 0.01, about 0.1, about 1.0%, and any amount between these amounts. In one aspect, a preservative can be included, for example, to prevent contamination of the multi-dose package.

Viscous agent

The compositions described herein may comprise a viscosity agent. Any suitable agent that increases the viscosity can be used. Increasing the viscosity to a simple aqueous solution may conveniently increase the ocular absorption of the active compound, reduce variations in the dispensing formulation, reduce physical separation of the components of the formulation suspension or emulsion, and/or otherwise improve the ophthalmic formulation. Such thickeners include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, and other fields. A reagent known to the skilled artisan, or a combination thereof. This reagent can be used in any suitable amount. The viscosity agent can be used in any suitable amount. In one aspect, the viscosity agent can be applied at a concentration level of from about 0.01% to about 2% by weight.

pH and buffer capacity (eg, storage conditions)

The present disclosure is useful for topical administration of any composition, such as topical administration to the eye, which may be formulated in water or other aqueous solvent having a pH of from about 4.5 to about 8. A buffer can be added to the solution to reach this pH range.

Compounds suitable as pH adjusting agents include, but are not limited to, glycerol buffer, citrate buffer, borate buffer, acetate buffer, gluconate buffer, phosphate buffer, or may also contain citric acid - Phosphate buffer.

Anesthetic

In one aspect, the compositions herein can also include an anesthetic (eg, an analgesic). Suitable analgesics are local anesthetics including, but not limited to, acetamidoeugenol, alfadolone acetate (alfadolone) Acetate), afaxalone, amucaine, amolaone, amylocaine, benoxinate, betoxcaine ), biphenamine, bupivacaine, burethamine, butacaine, butamben, butanilicaine, buthalital ), butoxycaine, cartamicine, 2-chloroprocaine, cinchocaine, cocaethylene, cocaine, Cyclomethycaine, dibucaine, dimethisoquin, dimethocaine, diperadon, dyclonine, buds (ecgonidine), ecgonine, ethyl urethane, ethyl chloride, etidocaine, etoxadrol, beta-eucaine, especially Euprocin, fenalcomine, fomocaine, hexobarbital, hexylcaine, hydroxy Hydroxydione, hydroxyprocaine, hydroxytetracaine, isobutyl p-aminobenzoate, kentamine, leucinocaine mesylate , levoxadrol, lidocaine, mepivacaine, meprylcaine, metabutoxycaine, methohexital, methyl chloride , midazolam, myrtecaine, naycaine (naepaine), octacaine, orthocaine, oxethazaine, parethoxycaine, phenacaine, phencyclidine (phencyclidine), phenol, piperocaine, piridocaine, polidocanol, pramoxine, prilocaine, procaine (procaine), propanidid, propanocaine, proparacaine, propipocaine, propofol, propoxycaine , pseudococaine, pyrrocaine, risocaine, salicyl alcohol, tetracaine, thirbarbital, thiopental (thimylal) ), thiobutabarbital, thiopental, tolycaine, trimecaine, zolamine, and combinations thereof. In this paper, tetracaine, lidocaine and prilocaine are called analgesics.

preparation

The ophthalmic composition can be in the form of a solution, suspension, emulsion, ointment, cream, gel or controlled release/sustained release vehicle. For example, the composition may be in the form of a contact lens solution, an eye wash, an ophthalmic drop, an ophthalmic gel, an ophthalmic ointment or the like. The containers of the disclosed compositions can be transparent, translucent, and opaque and can contain other properties or combinations of properties such as glass lining, tamper resistance, aliquoting in single or multiple doses, and combinations thereof.

Any group of compositions mentioned anywhere in this disclosure The fraction (eg, chlorhexidine, anti-inflammatory, preservative, co-solvent or viscosity) may be in a chemically equivalent form such as a salt, hydride, ester, and other modifications of the base chemical. For example, prednisolone acetate can be replaced with any derivative or salt of prednisolone acetate in any of the compositions or methods of the present disclosure.

method

The present disclosure provides, as described above, a method of treating and/or preventing an ocular disease or infection via administration of an ophthalmic composition as described herein. This ophthalmic composition is also suitable for infective prevention and inflammation control in patients undergoing ophthalmic surgery recovery. In one aspect, the present disclosure provides a method of treating and/or preventing a disease or infection (including, eg, an ocular disease or infection) in a subject, administering an effective amount to a subject in need thereof, comprising chlorhexidine and an antibiotic An inflammatory agent is administered to a subject comprising a chlorhexidine, a derivative or analog of chlorhexidine, or a pharmaceutically active salt, solvent, hydrate or allotrope thereof as an active agent and an anti-inflammatory agent. To treat or prevent eye diseases or infections.

An ocular condition that can be treated with an ophthalmic composition can include, for example, conjunctivitis, tendonitis, or keratitis. Furthermore, the amount of the ophthalmic composition can be an amount effective to prevent or treat the infection after surgery.

The ophthalmic composition for treating or preventing an ocular disease or infection can be formulated into a solution, suspension, semi-liquid, emulsion, ointment, cream, foam gel, powder or controlled release/sustained release formulation.

When the composition for topical administration is formed, the composition can be formulated into an aqueous solution of 0.01 to 2.0% by weight and a pH of 4.5 to 8.0.

The disclosed compositions can be applied topically to the eye. Dosages can range from about 0.001 mg to about 5.0 mg per eye. In one aspect, each eye dose can be about 1 drop of solution which corresponds to from about 50 μl to about 80 μl of solution.

The composition may be applied topically by placing 1 to 2 drops or more per eye, 1 to 24 times per day. For example, the composition can be administered 1, 2, 3, 4 or 8, 12, 18 or 24 times or more per day. In one embodiment, the disclosed compositions are topically applied by placing 1 to 2 drops of 1 to 2 times per eye per eye.

The ophthalmic composition can be tested in a selected animal model. For example, a derivative or analog comprising chlorhexidine, chlorhexidine, or a pharmaceutically acceptable salt, solvent, hydrate or allotrope of a chlorhexidine, or a derivative thereof, may be used in an animal model. The efficacy, toxicity, or side effects of treatment with the composition are determined by the composition of the analog or anti-inflammatory agent. Alternatively, the mechanism of action of the agent can be determined using the composition in an animal model.

Certain specific examples have been described herein to illustrate the disclosure. However, it will be apparent that the present disclosure is not limited thereto, as other variations will be apparent to those skilled in the art. Any of the compositions or methods provided herein can be combined with one or more of any of the other compositions and methods provided herein. Other features and benefits of the compositions and methods described herein will be apparent to those skilled in the art from the <RTIgt; All patents, patent applications, and references cited herein are hereby incorporated by reference in their entirety herein.

Those skilled in the art will understand or be able to use no more routine experimentation to determine many equivalents of the specific embodiments described herein. Things. These equivalents are intended to be included in the scope of the following claims.

[Examples] Example 1: Production of chlorhexidine and anti-inflammatory composition

Chlorhexidine and anti-inflammatory agents solutions were prepared using standard protocols. Briefly, excipients are separately added to pure warm water (about 50 ° C) in appropriately sized containers such as beakers. Excipients include preservatives (eg, hydroxychloroaniline), cosolvents (eg, polysorbate 80), disinfectants (eg, boric acid), and antioxidants (eg, ascorbic acid). The solution was stirred to mix all the excipients. An anti-inflammatory agent is then added. If the anti-inflammatory agent is insoluble or poorly soluble in water (e.g., prednisolone acetate) is then wetted with a solution of the dispersing agent in a suitable rheology modifiers, such as cellulose ethers, such as, METHOCEL ^TM E4M . The solution was mixed until homogeneous and there was no agglomeration. Chlorhexidine gluconate is then added and stirring is continued. The pH of the solution is checked and adjusted to about neutral pH (pH 7.0 to 7.5) if necessary.

Transfer the prepared solution to a suitably sized bottle/vial (with stirring during transfer). The vial is crimped and sealed and then autoclaved using standard sterilization techniques. If necessary, sonicate the vial after sterilization to break any agglomerated material.

In one embodiment, the solution contains prednisolone acetate (1%) and chlorhexidine (0.2%) and the following additives: polysorbate 80 (0.2%), boric acid (1.7%), ascorbic acid (0.1) %), Methocel® E4M Premium CR (0.4%), hydroxychloroaniline (1.1%).

Stability test

6 months dark storage period using standard HPLC technology To evaluate the chemistry of chlorhexidine and prednisolone prepared above at various temperatures (eg, 5 ° C, 25 ° C, 40 ° C) and relative humidity ("RH") (eg, 25%, 40%) stability. The results show that the test solution has acceptable chlorhexidine and prednisolone stability.

Prednisolone and chlorhexidine for 6 months stability test

Standard HPLC techniques were also used during the 3 month storage period to evaluate the addition of chlorhexidine (0.2%) to difluoride at various temperatures (eg, 25 ° C, 40 ° C) and relative humidity (eg, 25%, 40%). chemical stability of the commercial formulations of prednisone ester (Durezol ^TM). The results showed some loss of difluprednate and chlorhexidine at 40 °C. You see the same result for the pouring Neumann carbonate (Lotemax ^TM) commercially available formulation chloride. It may be that the positively charged chlorhexidine in the commercially available formulation is mismatched with the negatively charged rheology modifier, and this can be solved by using a suitable nonionic rheology modifier such as hydroxyethyl cellulose. (The prednisolone solution shown above).

Stability test of Durezol (difluprednate) and chlorhexidine for 3 months

Example 2: Antibacterial test

The effectiveness of the self-storing solution was demonstrated using a standardized antibacterial effect test (AET) to detect solutions of chlorhexidine and various anti-inflammatory agents. The study evaluated formulations in a neutralizer and recovery control test using 10-100 cfu of USP-designated organisms, Staphylococcus aureus, Pseudomonas syringae, Escherichia coli, Candida albicans, and Aspergillus brasiliensis . . This test is an effective method to test the antibacterial effect of USP.

The two formulations of 1% prednisolone acetate ophthalmic suspension and 0.2% chlorhexidine gluconate were confirmed by the USP antibacterial effect test (neutralization efficacy). 1 mL of Saline-TS was added to 9 mL of DEB as a negative control (NC). A 1 mL sample of the product was added to 9 mL of DEB as a sample negative control (SNC). Each challenge organism (S. aureus ATCC 6538, Pseudomonas syringae ATCC 9027, E. coli ATCC 8739, Candida albicans ATCC 10231, and Aspergillus oryzae ATCC 16404) was prepared to contain 1.0 X 10 ³ and 1.0 X 10 ⁴ cfu. Concentration between /mL and in the inoculation tube 100 cfu/mL. 100 μL aliquots of challenge organisms were added to 1 mL of Saline-TS and 9 mL of DEB with two replicates as positive controls (PC). Add the biological challenge component 100 μ L to 1mL of product samples and 9mL of DEB as to repeat the two test samples (S1 and S2). 1 mL of the component was repeatedly plated from each PC and TS tube. Pour SCDA into PC and TS plates with Pseudomonas syringae, Escherichia coli and Staphylococcus aureus and incubate at 32.5 °C ± 2.5 °C for 3 to 5 days while pouring SDA into Candida albicans and Aspergillus oryzae plates. Incubate for 3 to 5 days (Candida albicans) and 3 to 7 days (Aspergillus Brazilian) at 22.5 ° C ± 2.5 ° C.

result

Note: The average count of PC and test samples is 10 to 100 cfu and the recovery of test samples is within 50% of the PC count. There is no growth on the NC plate. SNC plates are for reference only.

Reference: LB599-007, LB599-009

The average values of the isolated colonies recovered from the PC and TS plates all fell between SOP-00181 and the range of 10 to 100 cfu specified in the "USP Antimicrobial Effect Test Category 1, 2, 3 and 4 Standard Terms" (refer to Table 2 and Table 3). ). The average recovery from the PC tube is at least 50% recovered from the TS tube. The NC plate did not grow. SNC plates are for reference only but have not grown. Based on these results, a formulation containing 1% prednisolone acetate ophthalmic suspension and 0.2% chlorhexidine gluconate was tested by a neutralization efficacy test and confirmed in the antibacterial effect test defined by USP 39/NF 34. The same formulation containing less chlorhexidine gluconate is also covered in this report.

Claims (36)

An ophthalmic composition comprising: a therapeutic active agent and an anti-inflammatory agent, wherein the active agent is at least about 0.01% w/v of chlorhexidine, a chlorhexidine derivative or the like, or a pharmaceutically acceptable agent thereof Accepted salts, solvents, hydrates or allotropes. The ophthalmic composition of claim 1, wherein the active agent has a concentration of from about 0.01% w/v to about 1.0% w/v. The ophthalmic composition of claim 1, wherein the active agent has a concentration of from about 0.01% w/v to about 0.5% w/v. The ophthalmic composition of claim 1, wherein the anti-inflammatory agent comprises a steroid anti-inflammatory or non-steroidal anti-inflammatory agent or both. The ophthalmic composition of claim 1, wherein the anti-inflammatory agent comprises dexamethasone, difluprednate, loteprednol, prednisolone acetate, ketotifen fumarate , diclofenac sodium, flurbiprofen sodium, ketorolac tromethamine, sulphonate, celecoxib, naproxen or rofecoxib, or a combination thereof. The ophthalmic composition of claim 1, wherein the anti-inflammatory agent has a concentration of from about 0.025% w/v to about 2.0% w/v. The ophthalmic composition of claim 1, further comprising a preservative. The ophthalmic composition according to claim 7, wherein the preservative comprises hydroxychloroaniline, thimerosal, chlorobutanol, methylparaben, propylparaben, phenylethyl alcohol, ethylenediamine. Disodium tetraacetate, sorbic acid or Onamr M, or a combination thereof. The ophthalmic composition of claim 1, further comprising a cosolvent. The ophthalmic composition of claim 9, wherein the co-solvent comprises polysorbate 20, polysorbate 60, polysorbate 80, Pluronic F-68, Pluronic F-84, Pluronic P -103 or cyclodextrin, or a combination thereof. The ophthalmic composition of claim 10, wherein the cosolvent is present in an amount from about 0.01% w/v to about 2.0% w/v. The ophthalmic composition of claim 1, further comprising a thickener. The ophthalmic composition of claim 12, wherein the viscous agent comprises polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethyl Cellulose or hydroxypropylcellulose, or a combination thereof. The ophthalmic composition of claim 13, wherein the viscous agent is present in an amount of from about 0.01% w/v to about 2.0% w/v. A method of treating or preventing an ocular disease or infection in a subject in need thereof, comprising: administering an ophthalmic composition comprising a therapeutic active agent and an anti-inflammatory agent to the eye of a subject in need thereof, wherein The active agent is at least about 0.01% w/v of chlorhexidine, a derivative or analog of chlorhexidine, or a pharmaceutically acceptable salt, solvent, hydrate or allomorph thereof; and the active agent thereof And the anti-inflammatory agent is present in an amount effective to treat or prevent an ocular disease or infection in the subject. The method of claim 15, wherein the ophthalmic composition is formulated into a solution, a suspension, a semi-liquid, an emulsion, an ointment, a cream, a foam gel, a powder or a controlled release/sustained release preparation. . The method of claim 15, wherein the ocular disease comprises conjunctivitis, gingivitis or keratitis. The method of claim 15, wherein the amount of the ophthalmic composition is effective for preventing or treating an infection after an ophthalmic surgery or an ophthalmic procedure. The method of claim 15, wherein the ophthalmic composition is administered topically. The method of claim 15, wherein the ophthalmic composition is administered to the eye at a concentration of from about 0.001 mg to about 5.0 mg of the active agent per eye. The application of the method of patentable scope of item 15, wherein each eye to about 50 μ L to about 80 L [mu] The amount of the ophthalmic composition is administered to the eye. The method of claim 15, wherein the source of the ocular disease or infection is bacteria, mycobacteria, mold, virus or amoeba. The ophthalmic composition according to claim 1, wherein the ophthalmic composition is formulated into a solution, a suspension, a semi-liquid, an emulsion, an ointment, a cream, a foam gel, a powder or a controlled release/ Sustained release of the formulation. The method of claim 15, wherein the active agent has a concentration of from about 0.01% w/v to about 1.0% w/v. The method of claim 15, wherein the active agent The concentration is from about 0.01% w/v to about 0.5% w/v. The method of claim 15, wherein the anti-inflammatory agent comprises a steroid anti-inflammatory agent or a non-steroidal anti-inflammatory agent or both. The method of claim 15, wherein the anti-inflammatory agent comprises dexamethasone, difluprednate, loteprednol, prednisolone acetate, ketotifen fumarate, diclofenac sodium. , flurbiprofen sodium, ketorolac tromethamine, sulphonate, celecoxib, naproxen or rofecoxib, or a combination thereof. The method of claim 15, wherein the anti-inflammatory agent has a concentration of from about 0.025% w/v to about 2.0% w/v. The ophthalmic composition further comprises a preservative, as in the method of claim 15. The method of claim 29, wherein the preservative comprises hydroxychloroaniline, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, ethylenediaminetetraacetic acid Sodium, sorbic acid or Onamr M, or a combination thereof. The method of claim 15, further comprising a cosolvent. The method of claim 15, wherein the co-solvent comprises polysorbate 20, polysorbate 60, polysorbate 80, Pluronic F-68, Pluronic F-84, Pluronic P-103 or Cyclodextrin, or a combination thereof. The method of claim 32, wherein the co-solvent is present in an amount from about 0.01% w/v to about 2.0% w/v. The ophthalmic composition further comprises a thickener as described in claim 15 of the patent application. The method of claim 34, wherein the viscosity agent comprises polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose or Hydroxypropyl cellulose, or a combination thereof. The method of claim 34, wherein the viscous agent is present in an amount from about 0.01% w/v to about 2.0% w/v.